Esters of 2-[(4-quinolyl)amino]-benzoic acids in analgesic and anti-inflammatory compositions

ABSTRACT

The compounds of the formula: ##STR1## in which R 1  is chlorine, CF 3 , or -SCF 3  and R 2  is phenyl or phenyl substituted by one or two Cl, CH 3 , CF 3 , OCF 3  or SCF 3  radicals, the phenyl being substituted when R 1  is chlorine, and their salts, having interesting analgesic and anti-inflammatory properties.

CROSS REFERENCE

This application is a division of application Ser. No. 457.174 filedApr. 2, 1974, now U.S. Pat. No. 3,935,229.

The present invention relates to esters of 2-[(4-quinolyl)amino]-benzoicacids and their addition salts with pharmaceutically tolerated acids,their preparation, and medicines containing them.

Such compounds are described in French Application 72/02,035 filed bySynthelabo on Jan. 21, 1972. They can be used as analgesic andanti-inflammatory medicines.

The present invention provides new 2-[(4-quinolyl)-amino]-benzoic acidesters which have markedly improved therapeutic properties. Thesecompounds have the formula ##STR2## in which R₁ represents a chlorineatom or a CF₃ or SCF₃ group, and R₂ represents a phenyl radical which isunsubstituted or substituted by one or two substituents chosen from Cl,CH₃, CF₃, OCF₃ and SCF₃, provided that the phenyl radical is substitutedwhen R₁ represents a chlorine atom. The invention also provides theaddition salts of the compounds of formula (I) with pharmaceuticallytolerated acids.

The compounds of the invention are prepared by a transesterificationreaction, which may be represented by the following equation: ##STR3##In these formulae R₁ and R₂ have the meanings given above and Rrepresents an allyl radical or, when R₁ represents SCF₃, a methylradical. The transesterification is advantageously carried out at theboiling point of an apolar solvent, for example, an aromatic hydrocarbonsuch as benzene, toluene, or xylene, in the presence of an alkali metalalcoholate and/or an alkali metal which reacts with the alcohol of theformula (III).

The compounds of the invention can also be prepared by a condensation inaccordance with the following equation: ##STR4##In these formulae, R₁and R₂ have the meanings given above and X representing a halogen atom,and preferably chlorine. This condensation is advantageously carried outat the reflux temperature of a polar solvent, and in particular in anoptionally acidified aqueous medium.

The following Examples illustrate the invention. The compounds ofExamples 1 to 20 were prepared by the transesterification process andthose of Examples 21 to 26 by the condensation process.

EXAMPLE 1 2-(4'-Phenyl-piperazino)-ethyl2-(7'-trifluoromethyl-thio-4'-quinolyl-amino)-benzoate and itsdihydro-chloride

[(I), R₁ = SCF₃ in the 7-position; R₂ = C₆ H₅ Code number: SL 72 -244 ]

A mixture of 18.9 g (0.05 mol) of methyl2-(7'-trifluoromethylthio-4'-quinolyl-amino)-benzoate, 15.95 g (0.075mol) of 2-(4'-phenyl-piperazino)-ethanol, 0.025 g of sodium and 100 mlof anhydrous toluene is heated at the reflux temperature for 5 hours,while the methanol formed during the reaction is slowly distilled. Aslight amount of insoluble matter is removed by hot filtration, and thetoluene is evaporated. The residual product is dissolved in methylenechloride, the solution obtained is washed several times with water,dried over anhydrous magnesium sulphate and filtered, and the solvent isevaporated from the filtrate. The oily product obtained is dissolved inboiling isopropanol, the solution is cooled, and the precipitate isfiltered off, washed with isopropyl alcohol and dried in vacuo. 20.2 g(yield = 73.1%) of 2-(4'-phenyl-piperazino)-ethyl2-(7'-trifluoromethylthio-4'-quinolyl-amino)-benzoate are collected;m.p. 120° C.

Analysis: C₂₉ H₂₇ F₃ N₄ O₂ S (M.W. = 552.62)

Base determination: Equivalent, calculated : 276.3 found: 281.9.

Its dihydrochloride is prepared by adding 40 ml. (0.04 mol) of Nhydrochloric acid to a solution of 11.05 g. (0.02 mol) of base in 70 ml.of methylene chloride. The salt which has separated out is filtered off,washed with water, dried and recrystallised from 250 ml. of ethanol. 9.5g. (yield = 76%) of light yellow 2-(4'-phenylpiperazino)-ethyl2-(7'-trifluoromethylthio-4'-quinolylamino)-benzoate dihydrochloride,m.p. 230°-232° C., are collected.

Analysis: C₂₉ H₂₉ Cl₂ F₃ N₄ O₂ S (M.W. = 625.54

Calculated %: C 55.68, H 4.67, N 8.96, F 9.11 Ionised Cl 11.33

Found %: 55.50 4.47 8.85 9.15 11.32 55.40 4.50 8.80 9.13.

EXAMPLE 2 2-(4'-m-Trifluoromethylphenyl-piperazino)-ethyl2-(7'-chloro-4'-quinolyl-amino)-benzoate and its dihydrochloride.

[(I); R₁ = Cl in the 7-position; ##STR5## code number: SL 72 -391 ].

A mixture of 17.3 g. (0.051 mol) of allyl2-(7'-chloro-4'-quinolyl-amino)-benzoate, 13.7 g. (0.05 mol) of2-(4'-m-trifluoromethylphenyl-piperazino)-ethanol, 100 ml. of anhydroustoluene and 0.03 g. of ethanol, 100 ml. of anhydrous toluene and 0.03 g.of sodium is heated at the reflux temperature, while the alcohol formedduring the reaction is slowly distilled off. Heating is continued untilthe starting ester has disappeared completely (as verified by thin layerchromatography), if necessary adding a little toluene to compensate forthat which is entrained during the distillation. After the end of thereaction, the solvent is evaporated and the residue is taken up inisopropyl alcohol. The solution crystallises on cooling. The crystalsare filtered off and dried, and 22.5 g. (yield = 80%) of2-(4'-m-trifluoromethylphenyl-piperazino)-ethyl2-(7'-chloro-4'-quinolylamino)-benzoate are finally collected, m.p.100°-102° C.

Analysis: C₂₉ H₂₆ ClF₃ N₄ O₂ (M.W. = 555)

Calculated %: Cl 6.39

Found %: 6.10 .

The dihydrochloride is prepared by adding 16 ml. of a 5N solution ofhydrochloric acid in ethanol to a solution of 22.20 g. (0.04 mol) of thebase in 200 ml. of methylene chloride. After the solvents have beenevaporated, the residue is crystallised from 250 ml. of isopropanol in21.95 g. (yield = 87.4%) of2-(4'-m-trifluoromethylphenyl-piperazino)-ethyl2-(7'-chloro-4'-quinolyl-amino)-benzoate dihydrochloride, m.p. 217° C.,are collected

Analysis: C₂₉ H₂₈ Cl₃ F₃ N₄ O₂ (M.W. = 627.93)

Calculated % (anhydrous): C 55.47, H 4.49, N 8.82, F 9.08. Taking intoaccount the 1.1% water content measured by a

Karl Fischer determination):

    ______________________________________                                                54.48        4.56      8.32    8.99                                   Found : 54.76        4.68      8.47    9.20                                           54.99        4.63      8.68    9.05                                   ______________________________________                                    

EXAMPLE 3 2-[4'-(2", 3"-Dimethyl-phenyl)-piperazino]-ethyl2-(7'-chloro-4'-quinolyl-amino)-benzoate and its dihydrochloride.

[(I); R₁ = Cl in the 7-position; ##STR6## Code number: SL 72 -248 ].

Following the procedure of Example 2, but starting from 16.9 g. (0.05mol) of allyl 2-(7'-chloro-4'-quinolyl-amino)-benzoate and 14 g. (0.06mol) of 2-[4'-(2", 3"-dimethylphenyl)-piperazino]-ethanol, 22.6 g.(yield = 87.9%) of 2-[4'-(2", 3"-dimethyl-phenyl)-piperazino]-ethyl2-(7'-chloro-4'-quinolyl-amino)-benzoate are obtained, m.p. 126° C.

Analysis: C₃₀ H₃₁ ClN₄ O₂ (M.W. 32 515.06)

Calculated %: Cl 6.89

Found %: 6.87

2-[4'-(2", 3"-Dimethyl-phenyl)-piperazino]-ethyl2-(7'-chloro-4'-quinolyl-amino)-benzoate dihydrochloride, prepared likethe dihydrochloride of Example 2, melts at 220° C.

Analysis: C₃₀ H₃₃ Cl₃ N₄ O₂ (M.W. = 587.98)

Calculated %: C 61.28, H 5.66, N 9.53, Ionised Cl 12.06

Found %: 61.15 5.75 9.46 12.03 61.18 5.73 9.40.

EXAMPLE 4 2-(4'-p-Chlorophenyl-piperazino)-ethyl2-(7'-chloro-4'-quinolyl-amino)-benzoate and its dihydrochloride

[(I); R₁ = Cl in the 7-position; ##STR7## Code number: RC 72 -165 ].

By following the procedure of Example 2 and reacting 16.9 g. (0.05 mol)of allyl 2-(7'-chloro-4'-quinolyl-amino)-benzoate and 24 g. (0.1 mol) of2-(4'-p-chlorophenyl-piperazino)-ethanol,2-(4'-p-chlorophenyl-piperazino)-ethyl2-(7'-chloro-4'-quinolylamino)-benzoate is prepared in a 60% yield, m.p.145° C.

Analysis: C₂₈ H₂₆ Cl₂ N₂ O₄ (M.W. = 521.45)

Calculated %: C1 13.61

Found %: 13.55.

2-(4'-p-Chlorophenyl-piperazino)-ethyl2-(7'-chloro-4'-quinolyl-amino)-benzoate dihydrochloride, prepared in anidentical manner to the dihydrochloride of Example 2, melts at 240° C.

Analysis: C₂₈ H₂₈ Cl₄ N₄ O₂ (M.W. = 594.37)

Calculated %: C 56.48, H 4.75, N 9.42, Cl 23.85

Found %: 56.45 4.60 9.39 23.60.

EXAMPLE 5 2-(4'-Phenyl-piperazino)-ethyl2-(7'-trifluoro-methyl-4'quinolyl-amino)-benzoate and itsdihydrochloride.

(I); R₁ = CF₃ in the 7-position; R₂ = C₆ H₅ Code number: SL 72 -242 ].

A mixture of 18.6 g. (0.05 mol) of allyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate, 14.4 g. (0.07 mol) of2-(4'-phenyl-piperazino)-ethanol, 100 ml. of anhydrous toluene and 0.02g. of sodium is heated for five hours at the reflux temperature, whilethe alcohol formed during the reaction is distilled off. The solution isallowed to cool, a slight amount of insoluble matter is filtered off,the toluene is evaporated from the filtrate, and the residue isdissolved in diethyl ether. The other solution is washed several timeswith water, dried over magnesium sulphate and filtered, the solvent isevaporated from the filtrate, and the remainly oily product is dissolvedin 200 ml. of boiling isopropyl alcohol. The solution is chilled, theprecipitate is filtered off, and 20.1 g. (yield = 79%) of2-(4'-phenylpiperazino)-ethyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate, m.p. 130° C., arefinally collected.

Analysis: C₂₉ H₂₇ F₃ N₄ O₂ (M.W. = 520.56)

Base determination: Equivalent, calculated 260.2

Found 257.

The dihydrochloride is prepared by adding 40 ml. of an N solution ofhydrochloric acid (0.04 mol) to 10.4 g. (0.02 mol) of base dissolved in50 ml. of methylene chloride. The precipitate is filtered off, dried andrecrystallised from 120 ml. of ethanol. 9.2 g. (yield = 78%) of2-(4'-phenyl-piperazino)-ethyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate dihydrochloride areobtained, m.p. 210° C.

Analysis: C₂₉ H₂₉ Cl₂ F₃ N₄ O₂ (M.W. = 593.48)

Calculated % (anhydrous) C 58.69, H 4.83, N 9.44, F 9.60 (Taking intoaccount the 0.7% water content measured by a

Karl Fischer determination):

    ______________________________________                                                58.27        4.97      9.37    9.53                                   Found % :                                                                             58.17        5.01      9.36    9.50.                                  ______________________________________                                    

EXAMPLE 6 2-(4'-m-Trifluoromethylphenyl-piperazino)-ethyl2-(4'-trifluoromethyl-4'-quinolyl-amino)-benzoate and itsdihydrochloride.

[(I); R₁ = CF₃ in the 7-position, ##STR8## Code number: SL 73.017].

A mixture of 18.65 g. (0.05 mol) of allyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate, 16.2 g. (0.059 mol)of 2-(4'-m-trifluoromethylphenyl-piperazino)-ethanol, 150 ml. ofanhydrous toluene and 0.03 g. of sodium is heated under reflux for twoand a half hours, while the allyl alcohol formed during the reaction isslowly removed by distillation. A slight amount of insoluble matter isfiltered off and the toluene is evaporated from the filtrate. Theresidue is dissolved in a mixture of methylene chloride an acetone (8:2)and this solution is passed through a silica column. Elution is carriedout with the same mixture of solvents and the eluate is collected in 50ml. fractions. These fractions are examined by thin layerchromatography. Those which contain into desired almost pure ester arecombined and the solvent is driven off from them. The residual productis triturated in a mixture of ether and petroleum ether, filtered offand dried. 16.8 g. (yield 32 57%) of2-(4'-m-trifluoromethylphenyl)-piperazino)-ethyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate, m.p. 88°-90° C., arethus isolated.

Analysis: C₃₀ H₂₆ F₆ N₄ O₂ (M.W. = 588.557)

Base determination: Equivalent calculated 294.2 found 298.

(Code number of the base: SL 73.033).

The dihydrochloride is prepared by dissolving 15.3 g. (0.026 mol) of theabove base in 75 ml. of methylene chloride and adding 13 ml. of a 4Naqueous solution of hydrochloric acid. The salt which has precipitatedis filtered off and recrystallised from isopropyl alcohol. 16.15 g.(yield = 94%) of 2-(4'-m-trifluoromethylphenyl-piperazino)-ethyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate dihydrochloride, m.p.230° C., are thus collected.

Analysis: C₃₀ H₂₈ Cl₂ F₆ N₄ O₂ (M.W. = 661.5)

Calculated %: C 54.47, H 4.27, N 8.47, Cl 10.72

Found %: 54.58 4.21 8.44 10.75.

EXAMPLE 7 2-(4'-m-Chlorophenyl-piperazino)-ethyl2-(7'-chloro-4'-quinolyl-amino)-benzoate and its dihydrochloride.

[(I); R₁ = Cl in the 7-position, ##STR9## Code number: SL 73-018].

16.9 g. (0.05 mol) of allyl 2-(7'-chloro-4'-quinolyl-amino)-benzoate and12.7 g. (0.0527 mol) of 2-(4'-m-chloro-phenyl-piperazino)-ethanol and150 ml. of anhydrous toluene are introduced into a 250 ml. distillationflask equipped with a magnetic stirrer. A few drops of toluene aredistilled off to entrain any traces of moisture, and 0.03 g. of sodiumare added. A slow distillation is then effected for three hours toremove the allyl alcohol as it is formed. Insoluble matter is removed byhot filtration, the toluene is vaporated from filtrate, and the residueis recrystallised from isopropyl alcohol. 22.85 g. (yield = 33%) of2-(4'-m-chlorophenylpiperazino)-ethyl2-(7'-chloro-4'-quinolyl-amino)-benzoate, m.p. 122° C., are collected.

Analysis: C₂₈ H₂₆ Cl₂ N₄ O₂ (M.W. = 521.4)

Base determination: Equivalent, calculated 521.4 found 522.

The dihydrochloride is prepared by dissolving 13.035 g. (0.025 mol) ofbase in 60 ml. of methylene chloride and adding 12.5 ml. of 4Nhydrochloric acid thereto. The dihydrochloride which has precipitated isfiltered off, washed with methylene chloride, dried in vacuo at 60° C.,and recrystallised from alcohol. It melts at 216° C.

Analysis: C₂₈ H₂₈ Cl₄ N₄ O₂ (M.W. = 594.37)

    ______________________________________                                        Calculated %:                                                                            C 56.58, H. 4.75, O 5.38, N 9.43                                              total       ionised                                                           Cl 23.86    Cl 11.93                                               Found %:   C 56.68, H  4.89, O 5.50, N 9.47                                              total       ionised                                                           Cl 23.75    Cl 11.95                                               ______________________________________                                    

EXAMPLE 8 2-(4'-m-Trifluoromethoxyphenyl-piperazino)-ethyl2-(7'-chloro-4'-quinolyl-amino)-benzoate and its dihydrochloride.

[(I); R₁ = Cl in the 7-position, ##STR10## Code number: SL 73.030].

A mixture of 16.9 g. (0.05 mol) of allyl2-(7'-chloro-4'-quinolyl-amino)-benzoate, 15.5 g. (0.0535 mol) of2-(4'-m-trifluoromethoxyphenyl-piperazino)-ethanol, 0.03 g. of sodiumand 100 ml. of anhydrous toluene is heated at the reflux temperature fortwo and a half hours, following the procedure of the proceedingExamples. After cooling, a slight amount of insoluble matter is filteredoff and the toluene is evaporated from the filtrate. The residue istaken up in an 8:2 mixture of methylene chloride and acetone and thissolution is chromatographed on a silica column. The fractions containingthe desired ester are combined and the solvents are driven off. 26.6 g.of oily aminoester are thus obtained.

The dihydrochloride is prepared therefrom by dissolving the aminoesterbase in methylene chloride and adding the calculated amount of 4Nhydrochloric acid solution in ethanol. Since the salt remains insolution, the solution is evaporated to dryness and the residue iscrystallised from isopropyl alcohol. 24 g. (yield: 74.5%) of2-(4'-m-trifluoromethoxyphenyl-piperazino)-ethyl2-(7'-chloro-4'-quinolyl-amino)-benzoate dihydrochloride, m.p.approximately 228° C., are obtained.

Analysis: C₂₉ H₂₈ Cl₃ F₃ N₄ O₃ (M.W. = 643.93)

Calculated %: C 54.09, H 4.38, N 8.70, Cl 11.01

Found %: 53.99 4.41 8.75 10.92.

EXAMPLE 9 2-(4'-m-Trifluoromethylthiophenyl-piperazino)-ethyl2-(7'-chloro-4'-quinolyl-amino)-benzoate and its dihydrochloride.

[(I); R₁ = Cl in the 7-position; ##STR11## Code number: SL 73 -031 ].

By following the procedure of the preceding Examples but using 22.36 g.(0.066 mol) of allyl 2-(7'-chloro-4'-quinolyl-amino)-benzoate, 21 g.(0.0685 mol) of 2-(4'-m-trifluoromethylthiophenyl-piperazino)-ethanol,34 g. of basic aminoester are obtained after chromatography on a silicacolumn and evaporation to dryness of the functions containing thedesired ester. The base is converted into its dihydrochloride by addingthe calculated amount of hydrochloric acid in ethanol to a solution ofthe base in methylene chloride. After evaporation of the solvents andrecrystallisation of the product from isopropyl alcohol, 32 g. (yield =73.6%) of 2-(4'-m-trifluoromethylthiophenyl-piperazino)-ethyl2-(7'-chloro-4'-quinolyl-amino)-benzoate dihydrochloride, m.p. 230° C.,are collected.

Analysis: C₂₉ H₂₈ Cl₃ F₃ N₄ O₂ S (M.W. = 659.99)

Calculated %: C 52.77; H 4.27, N 8.48, Cl⁻¹⁰.74

Found %: 52.70 4.27 8.39 10.66

EXAMPLE 10 2-(4'-m-Chlorophenyl-piperazino)-ethyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate and itsdihydrochloride.

[(I); R₁ = CF₃ in the 7-position, ##STR12## Code number: SL 73 -045 ].

By reacting a mixture of 11.2 g. (0.0465 mol) of2-(4'-m-chlorophenyl-piperazino)-ethanol and 15.58 g. (0.0419 mol) ofallyl 2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate in toluene, andby following the procedure of the proceding Examples, a solid isobtained after removing the solvent, and this solid is recrystallisedfrom isopropyl alcohol. 13.2 g. (yield = 65%) of2-(4'-m-chlorophenyl-piperazino)-ethyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate, m.p. 125° C., arethus collected.

Analysis: C₂₉ H₂₆ ClF₃ N₄ O₂ (M.W. = 555)

Calculated %: C 62.76, H 4.72, N 10.09

Found %: 62.84 4.67 9.88.

The dihydrochloride is prepared by dissolving the above base inmethylene chloride, and adding the calculated amount of a 4N solution ofhydrochloric acid in ethanol. The solvents are evaporated and thedihydrochloride is recrystallised from isopropanol.2-(4'-m-Chlorophenyl-piperazino)-ethyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate dihydrochloride meltswith decomposition at 240° C.

Analysis: C₂₉ H₂₈ Cl₃ F₃ N₄ O₂ (M.W. = 627.9)

    ______________________________________                                        Calculated % : C 55.47, H 4.49, N 8.92                                                       ionised    total                                                              Cl 11.31   Cl 16.94 F 9.08                                     Found % :      C 55.54, H 4.72 N 8.79                                                        ionised    total                                                              Cl 11.35   Cl 17.07 F 9.04.                                    ______________________________________                                    

EXAMPLE 11 2-[4'-(3"-Chloro-2"-methyl-phenyl)-piperazino]-ethyl2-(7'-chloro-4'-quinolyl-amino)-benzoate and its dihydrochloride.

[(I); R₁ = Cl in the 7-positon, ##STR13## Code number: SL 73 -046 ].

Using the procedure of the preceding Examples, 9.5 g. (0.0373 mol) of2-[4'-(3"-chloro-2"-methyl-phenyl)-piperazino]-ethanol and 11.8 g.(0.035 mole) of allyl 2-(7'-chloro-4'-quinolyl-amino)-benzoate arereacted in toluene. The solvent is evaporated and the oily residue istriturated in petroleum ether until solidification takes place. Theproduct is filtered off, dried in air and recrystallised from isopropylalcohol. 15.15 g. (yield = 81%) of2-[4'-(3"-chloro-2"-methyl-phenyl)-piperazino]-ethyl2-(7'4'-quinolyl-amino)-benzoate, m.p. 122° C., are thus collected

Analysis: C₂₉ H₂₈ Cl₂ N₄ O₂ (M.W. = 535.38)

Calculated %: C 65.06, H 5.27, N 10.46

Found %: 65.00 5.29 10.44.

The dihydrochloride is prepared by dissolving the above base inmethylene chloride and adding a calculated amount of 4N hydrochloricacid in ethanol. The solvents are evaporated and the dihydrochloride isrecrystallised from isopropyl alcohol. The2-[4'-(3"-chloro-2"-methyl-phenyl)-piperazino]-ethyl2-(7'-chloro-4'-quinolyl-amino)-benzoate dihydrochloride obtained meltswith decomposition at 210° C.

Analysis: C₂₉ H₃₀ Cl₄ N₄ O₂ (M.W. = 608.3)

total

Calculated %: C 56.34, H 5.07, O 6.58, N 9.06 Cl 22.95

Found %: 56.50 4.96 6.49 9.18 22.79.

Calculated by taking into account a 1.5% water content measured by theKarl Fischer method.

EXAMPLE 12 2-[4'-(3"-chloro-2"-methyl-phenyl)-piperazino]-ethyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-bezoate and itsdihydrochloride.

[(I); R₁ = CF₃ in the 7-position; ##STR14## Code number: SL 73 -047 ].

A mixture of 5.4 g. (0.021 mol) of2-[4'-(3"-chloro-2"-methyl-phenyl)-piperazino]-ethanol and 7.5 g. (0.02mol) of allyl 2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate isreacted in toluene, following the procedure of the preceding Examples.The toluene is evaporated and the residue is crystallised from petroleumether. The crystals are filtered off, dried in air and recrystallisedfrom isopropyl alcohol. 10.5 g. (yield = 92%) of2-[4'-(3"-chloro-2"-methyl-phenyl)-piperazino]-ethyl2-(7'-trifluoromethyl-4"-quinolyl-amino)-benzoate, m.p. 130° C., arethus obtained.

Analysis: C₃₀ H₂₈ ClF₃ N₄ O₂ (M.W. = 569.03) Calculated %: C 62.32, H4.96, N 9.85

Found %: 63.36 5.14 9.84.

The dihydrochloride is prepared by dissolving the base in methylchloride and adding a calculated amount of a 4N solution of hydrochloricacid in ethanol. The dihydrochloride is filtered off and recrystallisedfrom isopropyl alcohol. 2-[4'-(3"-methyl-phenyl)-piperazino]-ethyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate dihydrochloride, m.p.230° C., with decomposition is thus obtained.

Analysis: C₃₀ H₃₀ Cl₃ F₃ N₄ O₂ (M.W. = 641.95)

Calculated %: C 56.04, H 4.88, N 8.72

Found %: 55.36 4.73 8.50

Calculated taking into account a 0.15% water content measured by theKarl Fischer method.

EXAMPLE 13 2-(4'-m-Trifluoromethylthiophenyl-piperazino)-ethyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate and itsdihydrochloride.

[(I); R₁ = CF₃ in the 7-position; ##STR15## Code number: SL 73 -048 ].

By reacting 12 g. (0.039mol) of2-(4'-m-trifluoromethylthiophenyl-piperazino)-ethanol and 13.9 g. (0.037mol) of allyl 2-(7'-trifluoromethyl-4'-quinolylamino)-benzoate intoluene, following the technique of the preceding Examples, an oil isobtained after evaporation of the solvent, and this oil ischromatographed on a silica column and eluted with a 4:1 mixture ofchloroform and actone. 20 g. (yield = 86%) of2-(4'-m-trifluoromethylthiophenyl-piperazino)-ethyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate are thus obtained as apale yellow oil.

Analysis: C₃₀ H₂₆ F₆ N₄ O₂ S (M.W. = 620.62)

Calculated %: C 58.06, H 4.22; N 9.03

Found %: 57.98 4.27 8.95.

The dihydrochloride is prepared by dissolving the oily base in methylenechloride and adding a calculated amount of a 4N solution of hydrochloricacid in ethanol. The solvents are vaporated and the residue isrecrystallised from isopropyl alcohol.2-(4'-m-Trifluoromethylthio-phenyl-piperazino)-ethyl2-(7'-trifluoromethyl-4'-quinolylamino)-benzoate dihydrochloride, m.p.220° C., with decomposition is thus obtained.

Analysis: C₃₀ H₂₈ Cl₂ F₆ N₄ O₂ S (M.W. = 693.54)

Calculated %: C 51.95, H 4.07, Cl 10.22

Found %: 51.94 4.00 10.14.

EXAMPLE 14 2-(4'-, -Trifluoromethoxyphenyl-piperazino)-ethyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate and itsdihydrochloride.

[(I); R₁ = CF₃ in the 7-position; ##STR16## Code number: SL 73 -051 ].

10.12 g. (0.035 mol) of2-(4'-m-trifluoromethoxy-phenyl-piperazino)-ethanol and 12.4 g. (0.0333mol) of allyl 2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate arereacted in toluene, following the procedure of the preceding Examples.The toluene is evaporated and the oil obtained is purified bychromatography on a silica column, eluting with a 9:1 mixture ofchloroform and acetone. The solvent is evaporated and 16.5 g. (yield =95%) of 2-(4'-m-trifluoromethoxyphenyl-piperazino)-ethyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate are obtained as an oilwhich cannot be crystallised.

Analysis: C₃₀ H₂₆ F₆ N₄ O₃ (M.W. = 604.56)

Calculated %: C 59.60, H 4.33, N 9.27

Found %: 59.35 4.26 9.10

The dihydrochloride is prepared by dissolving the above base inmethylene chloride and adding a calculated amount of a 4N solution ofhydrochloric acid in ethanol. The solvents are evaporated, the residueis riturated in diethyl ether and the2-(4'-m-trifluoromethoxyphenyl-piperazino)-ethyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate dihydrochlorideobtained is recrystallised from isopropyl alcohol. It then melts at270°-272° C., with decomposition.

Analysis: C₃₀ H₂₈ Cl₂ F₆ N₄ O₃ (M.W. = ]677.48) Calculated %: C 53.19, H4. 17, N 8.27, F 16.82, Cl 10.47 Found %: 53.17 4.11 8.13 16.69 10.52.

EXAMPLE 15 2-(4'-m-Trifluoromethylthiophenyl-(piperazino)-ethyl2-(7'-trifluoromethylthio-4'-quinolyl-amino)-benzoate and itsdihydrochloride.

[(I); R₁ = SCF₃ in the 7-position; ##STR17## Code number: SL 73-069].

Using the procedure of the preceding Examples, a mixture of 11.35 g.(0.03 mol) of methyl2-(7'-trifluoromethyl-thio-4'-quinolyl-amino)-benzoate, 9.8 g. (0.032mol) of 2-(4'-m-trifluoromethylthiophenyl-piperazino)-ethanol, 150 ml.of toluene and 0.03 g. of sodium is heated for three hours. The oil ispurified by chromatography on a silica column and the pure oily baseobtained is crystallised by trituration in petroleum ether. 15.9 g.(yield = 81%) of 2-(4'-m-trifluoromethylthio-phenyl-piperazino)-ethyl2-(7'-trifluoromethylthio-4'-quinolyl-amino)-benzoate are thus obtained.After recrystallisation from isopropyl alcohol, it melts and 90° C.

Analysis: C₃₀ H₂₆ F₆ N₄ O₂ S₄ (M.W. = 652.69) Calculated %: C 55.20, H.4.01, N 8.58 Found %: 54.62 4.00 8.46.

2-(4'-m-Trifluoromethylthiophenyl-piperazino)-ethyl2-(7'-trifluoromethylthio-4'-quinolyl-amino)-benzoate dihydrochloride,prepared as in the preceding Examples, melts at 220° C., afterrecrystallisation from ethyl alcohol.

Analysis: C₃₀ H₂₈ Cl₂ F₆ N₄ O₂ S₂ (M.W. = 725.61) Calculated %: C 49.60,H 3.89, N 7.72, Cl 9.77 Found %: 49.58 3.85 7.59 9.81

EXAMPLE 16 2-[4'-(3",5"-Di-trifluoromethyl-phenyl)-piperazino]-ethyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate and itsdihydrochloride.

[(I); R₁ = CF₃ in the 7-position; ##STR18## Code number: SL 73-070].

By heating 11.17 g. (0.03 mol) of allyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate, 11.3 g. (0.33 mol) of2-[4'-(3",5"-di-trifluoromethyl-phenyl)-piperazino]-ethanol, 150 ml. oftoluene and 0.03 g. of sodium for two hours thirty minutes, 16.7 g.(yield = 85%) of2[4'-(3",5"-di-trifluoromethyl-phenyl)-piperazino]-ethyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate are obtained after theusual treatment, and this product, after recrystallisation fromisopropyl alcohol, melts at 114° C.

Analysis: C₃₁ H₂₅ F₉ N₄ O₂ (M.W. = 656.58) Calculated %: C 56.71, H3.83, N 8.53 Found %: 56.76 3.93 8.67

2-[4'-(3",5"-Di-trifluoromethyl-phenyl)-piperazino]-ethyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate dihydrochloride,prepared as in the preceding Examples, melts at 238° C., afterrecrystallisation from ethyl alcohol.

Analysis: C₃₁ H₂₇ Cl₂ F₉ N₄ O₂ (M.W. = 729.48) Calculated %: C 51.04, H3.73, N 7.68 Found %: 51.08 3.70 7.64.

EXAMPLE 17 2-(4'-m-Trifluoromethylphenyl-piperazino)-ethyl2-(8'-trifluoromethyl-4'-quinolyl-amino)-benzoate.

(R₁ = CF₃ in the 8-position; ##STR19## Code number: SL B 179).

10.76 g. (0.0289 mol) of allyl2-(8'-trifluoromethyl-4'-quinolyl-amino)-benzoate, 8.23 g. (0.03 mol) of2-(4'-m-trifluoromethylphenyl-piperazino)-ethanol and 150 ml. ofanhydrous toluene are introduced into a distillation apparatus. Themixture is heated at the reflux temperature, and approximately 10 ml. oftoluene are slowly distilled in order to entrain traces of water presentin the reaction mixture. 0.06 g. of sodium is then added and the wholeis heated for 3 hours with continuous slow distillation to remove theallyl alcohol formed during the trans-esterification reaction. Thedisappearance of the starting ester is checked by thin layerchromatography. The boiling reaction mixture is filtered to remove aslight amount of insoluble matter and the toluene is evaporated from thefiltrate. A gummy residue is obtained and is triturated in petroleumether. The precipitate which separates out is filtered off, washed withpetroleum ether, dried in vacuo and recrystallised from isopropylalcohol. 13.8 g. (yield = 81%) of2-(4'-m-trifluoromethylphenyl-piperazino)-ethyl2-(8'-trifluoromethyl-4'-quinolyl-amino)-benzoate, m.p. 114° C., areobtained.

Analysis: C₃₀ H₂₆ F₆ N₄ O₂ (M.W. = 588.557) Calculated %: C 61.22, H4.45, N, 9.52 Found %: 61.01 4.72 9.40.

EXAMPLE 18 2-(4'-m-Chlorophenyl-piperazino)-ethyl2-(8'-trifluoromethyl-4'-quinolyl-amino)-benzoate

(R₁ = CF₃ in the 8-position; ##STR20## Code number: SL B 180).

A mixture of 10.76 g. (0.0289 mol) of allyl2-(8'-trifluoromethyl-4'-quinolyl-amino)-benzoate, 7.21 g. (0.03 mol) of2-(4'-m-chlorophenyl-piperazino)-ethanol, 0.07 g. of sodium and 150 ml.of anhydrous toluene is heated at the reflux temperature for 3 hours,following the procedure described in Example 17. The reaction mixture isfiltered hot, and the toluene is evaporated from the filtrate. Theresidual paste-like product is triturated in petroleum ether and theprecipitates which separates out is filtered off, washed, dried in vacoand recrystallised from ethanol. 13 g. (yield = 81%) of2-(4'-m-chlorophenyl-piperazino)-ethyl2-(8'-trifluoromethyl-4'-quinolyl-amino)-benzoate, m.p. 140° C., areobtained.

Analysis: C₂₉ H₂₆ ClF₃ N₄ O₂ (M.W. = 555.04) Calculated %: C 62.76, H4.72, N 10.09, Cl 6.39 Found %: 62.68 4.75 9.96 6.46 6.30.

EXAMPLE 19 2-(4'-Phenyl-piperazino)-ethyl2-(8'-trifluoromethyl-4'-quinolyl-amino)-benzoate.

(R₁ = CF₃ in the 8-position; R₂ = C₆ H₅ Code number: SL B 181).

Following the technique of Examle 17, a mixture of 10.76 g. (0.0289 mol)of allyl 2-(8'-trifluoromethyl-4'-quinolyl-amino)-benzoate, 7.426 g.(0.036 mol) of 2-(4'-phenyl-piperazino)-ethanol, 0.07 g. of sodium and150 ml. of toluene is heated at the reflux temperature for approximately3 hours. The reaction mixture is filtered and the toluene is evaporatedfrom the filtrate. A solid residue is obtained which is washed withwater, dried in vacuo and recrystallised from 2-propanol. 13 g. (yield =86%) of 2-(4'-phenyl-piperazino)-ethyl2-(8'-trifluoromethyl-4'-quinolyl-amino)-benzoate, m.p. 147° C., arethus obtained.

Analysis: C₂₉ H₂₇ F₃ N₄ O₂ (M.W. 520.559) Calculated %: C 66.91, H 5.61,N 10.76 Found %: 66.84 5.44 10.76 66.89 5.50.

EXAMPLE 20 2-(4'-m-Trifluoromethylthiophenyl-piperazino)-ethyl2-(8'-trifluoromethyl-4'-quinolyl-amino)-benzoate

(R₁ = CF₃ in the 8-position; ##STR21## Code number: SLB 182).

Following the procedure of Example 17, a mixture of 10.76 g. (0.0289mol) of allyl 2-(8-trifluoromethyl-4-quinolyl-amino)-benzoate, 10.11 g.(0.033 mol) of 2-(4-m-trifluoromethylphenyl-piperazino)-ethanol, 0.05 g.of sodium and 150 ml. of toluene is heated at the reflux temperature for2 hours 30 minutes. The hot mixture is filtered, the toluene isevaporated from the filtrate and the gummy residue is triturated inpetroleum ether. The precipitate which separates out is filtered off,dried in vacuo and recrystallised from 2-propanol. 15.6 g. (yield = 86%)of 2-(4'-m-trifluoromethylthiophenyl-piperazino)-ethyl2-(8'-trifluoromethyl-4'-quinolyl-amino)-benzoate, m.p. 128° C., areobtained.

Analysis: C₃₀ H₂₆ F₆ N₄ O₂ S (M.W. = 610.621) Calculated %: C 58.06, H4.22, N 9.03 Found %: 57.97 4.35 8.96.

EXAMPLE 21 2-(4'-m-Trifluoromethylphenyl-piperazino)-ethyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate

[(I), R₁ = -CF₃ in the 7-position, ##STR22##

9.23 g. (0.0235 mol) of 2-(4'-m-trifluoromethylphenyl-piperazino)-ethyl2-amino-benzoate, 7 g. (0.03 mol) of4-chloro-7-trifluoromethyl-quinoline, 100 ml. of water and 20 ml. of 2Nhydrochloric acid are introduced into a 250 ml. flask. This mixture isheated at the reflux temperature for two hours. The reaction mixture isallowed to cool, neutralised with a saturated solution of sodiumbicarbonate, and extracted with methylene chloride. The organic phase isdecanted, washed with water, dried over magnesium sulphate and filtered.The solvent is driven off from the filtrate and the residual solid istriturated in petroleum ether. The precipitate is filtered off andrecrystallised from isopropyl alcohol.

10.95 g. (yield = π79.1%) of2-(4'-m-trifluoromethyl-phenyl-piperazino)-ethyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate, m.p. 88°-90° C., arethus obtained.

EXAMPLE 22 2-(4'-m-Trifluoromethylphenyl-piperazino)-ethyl2-(7'-chloro-4'-quinolyl-amino)-benzoate

[(I) R₁ = Cl in the 7-position, ##STR23##

11.65 g. (0.025 mol) of 2-(4'-m-trifluoromethylphenyl-piperazino)-ethyl2-amino-benzoate dihydrochloride are added to a suspension of 4.95 g.(0.025 mol) of 4,7-dichloro-quinoline in 100 ml. of water, and thismixture is heated at the reflux temperature for two hours. A further4.95 g. (0.025 mol) of 4,7-dichloro-quinoline are added, and heating iscontinued until the reaction is complete. The mixture is cooled, and theprecipitate which has formed is filtered off, washed with water, driedand recrystallised from isopropyl alcohol. 10.5 g. (yield = 66.8%) of2-(4'-m-trifluoromethyl-phenyl-piperazino)-ethyl2-(7'-chloro-4'-quinolyl-amino)-benzoate dihydrochloride are thusobtained.

The base is liberated by adding a saturated solution of sodiumbicarbonate to a suspension of this dihydrochloride in water, andextraction with methylene chloride. The organic layer is isolated,washed several times with water, dried over magnesium sulphate andfiltered. The solvent is evaporated from the filtrate and the solidresidue is recrystallised from isopropyl alcohol. 6.75 g. (yield =72.6%) of 2-(4'-m-trifluoromethyl-phenyl-piperazino)-ethyl2-(7'-chloro-4'-quinolyl-amino)-benzoate, m.p. 100°-102° C., areobtained.

EXAMPLE 23 2-(4'-m-Chlorophenyl-piperazino)-ethyl2-(7'-chloro-4'-quinolyl-amino)-benzoate

[(I), R₁ = Cl in the 7-position, ##STR24##

12.5 ml. of 2N hydrochloric acid are added to suspension of 6.44 g.(0.0325 mol) of 4,7-dichloro-quinoline and 9 g. (0.025 mol) of2-(4'-m-chlorophenyl-piperazino)-ethyl anthranilate in 75 ml. of water.This mixture is heated at the reflux temperature for three hours, andthen allowed to cool. The base is liberated by adding a saturatedsolution of sodium bicarbonate, and extracted with methylene chloride.The organic solution is decanted, washed several times with water, driedover sodium sulphate and filtered. The solvent is driven off from thefiltrate and the residue is recrystallised from isopropyl alcohol. 9.95g. (yield = 76.4%) of 2-(4'-m-chlorophenyl-piperazino)-ethyl2-(7'-chloro-4'-quinolyl-amino)-benzoate, m.p. 122° C., are collected.

EXAMPLE 24 2-(4'-m-Trifluoromethylthiophenyl-piperazino)-ethyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate

[(I), R₁ = -CF₃ in the 7-position, ##STR25##

A suspension of 5.80 g. (0.025 mol) of4-chloro-7-trifluoromethyl-quinoline and 9.96 g. (0.02 mol) of2-(4'-m-trifluoromethylthiophenyl-piperazino)-ethyl 2-amino-benzoatedihydrochloride in 100 ml. of water is heated at the reflux temperaturefor four hours. The reaction mixture is cooled, and the precipitate isfiltered off, washed with water, dried in vacuo in the presence ofphosphorus pentoxide and recrystallised from isopropyl alcohol.

10.7 g. (yield = 77.4%) of2-(4'-m-trifluoromethylthiophenyl-piperazino)-ethyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate dihydrochloride, m.p.220° C., are obtained.

To obtain the base, a solution of sodium bicarbonate is added to thesuspension of the dihydrochloride in water and the mixture is extractedwith methylene chloride. The organic layer is washed with water, driedover sodium sulphate and filtered. The solvent is evaporated from thefiltrate, and the base is obtained as an oil, which is purified bypassage through a silica column (eluant,chloroform-acetone: 80-20).After evaporation of the solvents, 7.85 g. (yield = 82%) of2-(4'-m-trifluoromethylthiophenyl-piperazino)-ethyl2-(7'-trifluoromethyl-4'-quinolyl-amino) benzoate are obtained as a paleyellow oil.

EXAMPLE 25 2-(4'-Phenyl-piperazino)-ethyl2-(8'-chloro-4'-quinolyl-amino)-benzoate

[(I), R₁ = Cl in the 8-position, R₂ = C₆ H₅ ]

4.95 g. (0.025 mol) of 4,8-dichloro-quinoline, 6.5 g. (0.02 mol) of2-(4'-phenyl-piperazino)-ethyl 2-amino-benzoate, 75 ml. of water and 10ml. of 2N hydrochloric acid are heated at the reflux temperature forthree hours. The base is liberated by adding a saturated solution ofsodium bicarbonate to the reaction mixture. The precipitate obtained isfiltered of, drained, washed several times with water, dried in vacuo inthe presence of phosphorus pentoxide, and recrystallised from ethanol.6.70 g. (yield = 68.7%) of 2-(4'-phenyl-piperazino)-ethyl2-(8'-chloro-4'-quinolyl-amino)-benzoate, m.p. 164° C., are thusobtained.

EXAMPLE 26 2-(4'-Phenyl-piperazino)-ethyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate

[(I), R₁ = CF₃ in the 7-position, R₂ = C₆ H₅ ].

23.1 g. (0.1 mol) of 4-chloro-7-trifluoromethyl-quinoline are added to asolution of 19.85 g. (0.05 mol) of 2-(4'-phenyl-piperazino)-ethyl2-amino-benzoate dihydrochloride in 500 ml. of methanol. The pH of themixture is adjusted to 2 by adding hydrocloric acid. The mixture isheated at the reflux temperature for eight hours. The mixture isfiltered, the methanol is evaporated and the residue is taken up in asaturated solution of sodium bicarbonate to liberate the base which isextracted with methylene chloride. The organic solution is washed withwater, dried over sodium sulphate and filtered. The solvent isevaporated from the filtrate, and the residue is recrystallised fromisopropyl alcohol. 13.5 g. (yield = 52%) of2-(4'-phenyl-piperazino)-ethyl2-(7'-trifluoromethyl-4'-quinolyl-amino)-benzoate, m.p. 130° C., areobtained.

The compounds of the invention possess valuable pharmacologicalproperties which make them useful for human and/or veterinary therapy.

Acute toxicity

Tests were carried out on mice of both sexes, of the Swiss strain, ofaverage weight 20 g. (± 2g.). The 50% lethal doses were calculatedaccording to Miller and Tainter (Proc. Soc. Exp. Biol. Med. 1944, 57,261). The results are given in Table I.

                  TABLE I                                                         ______________________________________                                                        ACUTE TOXICITY, MICE,                                         COMPOUND        ORAL ADMINISTRATION                                           CODE NO.        LD50* mg/kg                                                   ______________________________________                                        72-165          >2,000                                                        72-242          >3,000                                                        72-244          1,200                                                         72-248          1,900                                                         72-391          2,500                                                         73-017          1,500                                                         73-018          4,000                                                         73-030          >4,000                                                        73-031          3,000                                                         73-033          4,000                                                         73-045          >4,000                                                        73-046          >2,000                                                        73-047          3,000                                                         73-048          4,000                                                         73-051          >4,000                                                        73-069          2,200                                                         73-070          >4,000                                                        SLB 179         >3,000                                                        SLB 180         >3,000                                                        SLB 181         2,000                                                         SLB 182         >3,000                                                        ______________________________________                                        Amidopyrine     850                                                           Phenylbutazone  600                                                           Glafenine       3,500                                                         ______________________________________                                         *LD50 = 50% lethal dose.                                                 

Analgesic Activity

This activity was investigated by two different methods:

1. Effect against pain induced, in Swiss mice, by the intraperitonealinjection of phenylquinone, in accordance with the experimentalprocedure of Siegmund (Proc. Soc. Exp. Biol. Med., 1957, 95, 729),modified by Cheymol (C.R. Soc. Diol., 1963, 157, 521) and Brittain(Nature, London, 1963, 20, 895). The results are given in Table IIbelow.

2. Tests using a plate heated by acetone vapours, carried out on Swissmice, in accordance with the description by Woolfe (J. Pharmacol. Exp.Therap., 1944, 80, 300) with the modifications by Chen (Science 1951,113, 631), Eddy (J. Pharmacol. Exp. Therap., 1953, 107, 385) andBoissier (Anesth. Analog., 1956, 13, 569).

Table III below gives the results obtained.

                  TABLE II                                                        ______________________________________                                                        SIEGMUND TEST, MICE,                                                          ORAL ADMINISTRATION                                           COMPOUND        AD50* mg/kg                                                   ______________________________________                                        72-165          50                                                            72-242          25                                                            72-244          10                                                            72-248          20                                                            72-391          20                                                            73-017          4                                                             73-018          6                                                             73-030          100                                                           73-031          100                                                           73-033          5                                                             73-045          8                                                             73-046          13                                                            73-047          16                                                            73-048          6                                                             73-051          16                                                            73-069          50                                                            73-070          16                                                            SLB 179         25                                                            SLB 180         12                                                            SLB 181         12                                                            SLB 182         5                                                             ______________________________________                                        Amidopyrine     50                                                            Phenylbutazone  90                                                            Glafenine       50                                                            ______________________________________                                         *AD50 = 50% active dose.                                                 

                  TABLE III                                                       ______________________________________                                                     HEATED PLATE TEST,                                                            MICE, ORAL ADMINI-                                               COMPOUND     STRATION MAD* mg/kg                                              ______________________________________                                        72-165       >300                                                             72-242       300                                                              72-244       300                                                              72-248       300                                                              72-391       150                                                              73-017        30                                                              73-018        60                                                              73-030       300                                                              73-031       200                                                              73-033        30                                                              73-045       150                                                              73-046       300                                                              73-047       300                                                              73-048       >200                                                             73-051       >200                                                             SLB 179      100                                                              SLB 180      300                                                              SLB 181      >300                                                             SLB 182      200                                                              ______________________________________                                        Amidopyrine  200                                                              Phenylbutazone                                                                             >200                                                             Glafenine    >600                                                             ______________________________________                                         *MAD = mean active dose.                                                 

The results obtained in the Siegmund test, which demonstrates analgesiceffects of the peripheral type, show that the compounds of the invention(72-242, 72-244, 72-248, 72-391, 73-017, 73-018, 73-033, 73-045, 73-046,73-047, 73-048, 73-051, SLB 179, 180, 181 and 182) are generally muchmore active than the well-known analgesic agents used for comparisonpurposes (amidopyrine and glafenine).

In the heated plate test, which demonstrates analgesic effects of thecentral type, the compounds (72-391, 73-017, 73-018, 73-033, 73-045 andSLB 179) show an activity which is greater than that of amidopyrine.This greater activity is considerable in the case of the compounds73-017, 73-018 and 73-033. In the case of the other compounds of theinvention, the central component is, as in the case of glafenine, muchless strong.

Anti-inflammatory activity

This activity was determined by the test involving oedema of the paw,induced in Sherman rats by the method of Winter and colleague (Proc.Soc. Exp. Biol. Med., 1962, 111, 544). The results are summarised inTable IV.

                  TABLE IV                                                        ______________________________________                                                     CARRAGENINE-INDUCED                                                           OEDEMA TEST, RATS, ORAL                                                       ADMINISTRATION                                                   COMPOUND     AD* mg/kg                                                        ______________________________________                                        72-242       40                                                               72-248       120                                                              72-391       40                                                               73-017       60                                                               73-018       120                                                              73-030       50                                                               73-031       30                                                               73-033       60                                                               73-045       30                                                               73-046       30                                                               73-047       65                                                               73-048       30                                                               73-051       50                                                               73-069       55                                                               73-070       >80                                                              SLB 179      120                                                              SLB 180      >100                                                             SLB 181      45                                                               SLB 182      150                                                              ______________________________________                                        Amidopyrine  80                                                               Phenylbutazone                                                                             30                                                               Glafenine    30                                                               ______________________________________                                         *AD40 = 40% active dose.                                                 

These results show that the compounds of the invention haveanti-inflammatory effects. These effects, which never exceed those ofphenylbutazone administered at the same dosage, must be considered bytaking into account the analgesic activity of the compounds of theinvention which manifests itself at doses very much lower that theanti-inflammatory doses.

These experimental data show that the invention provides compoundshaving a very marked dissociation between analgesic andanti-inflammatory properties, in favour of the analgesic activity. Thisdissociation is of great value when it is considered thatanti-inflammatory activity is frequently associated with mediocre ordistinctly poor tolerance by the mucous membranes of the digestivetract.

Finally, and surprisingly, the toxicity of the majority of the compoundsof the invention virtually does not increase at all with their activity,so that their therapeutic index is very much greater than that ofglafenine.

The results show that the compounds of the invention can be used inhuman and veterinary therapy, and especially in the treatment of variousalgias, especially if they accompany inflammatory affections. The methodof administration can be oral, rectal or parenteral, the activesubstances being used in conjunction with the usual excipients for thesepharmaceutical forms. In the case of oral administration, for whichtablets, dragees, capsules, gelatine-coated pills, potable solutions andthe like, are used, the unit dose is 20 to 200 mg, the maximum dailydosage being 1 g. In the case of rectal administration, these figuresare, respectively, from 50 to 400 mg. and 1 g., and in the case ofparenteral administration, they are, respectively from 10 to 50 mg. and0.5 g.

The invention accordingly includes within its scope pharmaceuticalcompositions comprising, in association with a compatiblepharmaceutically acceptable diluent, a compound of formula I or apharmaceutically tolerated acid addition salt thereof.

We claim:
 1. An analgesic and anit-inflammatory composition comprisingan analgesic or anti-inflammatory effective amount of a compound of theformula: ##STR26##wherein R₁ is chlorine, trifluoromethyl ortrifluoromethylthio; andR₂ is phenyl, chlorophenyl, methylphenyl,trifluoromethylphenyl, trifluoromethoxyphenyl,trifluoromethylthiophenyl, dimethylphenyl, chloromethylphenyl orditrifluoromethylphenyl, R₂ being a substituted phenyl when R₁ ischlorine,or of a pharmaceutically acceptable acid addition salt thereofin combination with a pharmaceutically acceptable diluent.
 2. Thecomposition of claim 1 wherein R₁ is trifluoromethyl.
 3. The compositionof claim 1 wherein R₁ is 7-trifluoromethyl and R₂ is ##STR27##